Multifocal extramedullary plasmacytomas (EMP) are an uncommon manifestation of plasma cell malignancies. We report two patients with multiple EMP who developed rapidly progressive and ultimately fatal disease shortly after undergoing nonmyeloablative, matched-related donor allogeneic peripheral blood stem cell transplantation (PBSCT). We have not observed a similar course in patients transplanted for multiple myeloma without extramedullary manifestations and hypothesize that the intense immunosuppression associated with the fludarabine, busulfan and anti-thymocyte globulin conditioning regimen may have contributed to rapid disease progression in the two EMP patients. Our observations support the assertion that extramedullary disease is a marker for an aggressive, refractory plasma cell malignancy and suggest that patients should be treated intensively from the time of diagnosis. The utility of a graft-versus-tumor effect and the role of nonmyeloablative allogeneic PBSCT is yet to be defined in patients with extramedullary plasma cell malignancies, but it is logical to consider using it at the time of minimal residual disease rather than at disease relapse or progression. Nevertheless, we recommend circumspection in the administration of highly immunosuppressive conditioning regimens to patients with refractory EMP and encourage further clinical research in this area.